Anaesthesia for In Vitro Fertilisation

Summary In vitro fertilization is an upcoming speciality. Anaesthesia duringassisted reproductivetechnique is generally required during oocyte retrieval, which forms one of the fundamental steps during the entire procedure. Till date variety of techniques likeconscious sedation, general anaesthesiaand regional anaesthesia hasbeen tried with none being superior to the other. However irrespective of thetechnique the key point of anaesthesiafor in vitro fertilization is to provide the anaesthetic exposure for least duration so as to avoid its detrimental effects on the embryo cleavage and fertilization.


Introduction
In-vitro fertilization(IVF) started 30 years back when Lesley and John Brown, a young couple from Bristol were unable to conceive for 9 years. Lesley had blocked Fallopian tubes. On 10 th Nov 1977, Lesley underwentthe very experimental in-vitrofertilization by Dr. Patrick Steptor. Finally, on 25 th July 1978LOUISE JOY BROWN, the 1 st successful test tube baby was born. Sincethen therehas been continuous refinement in the fertility drugprotocols and the techniques to retrieve eggs. As a result, IVF success rates began to climb slowly reaching 25-30% 1

What is In-Vitro Fertilization?
In-Vitro Fertilization is a broad term for the technique of ultrasound directed Oocyte retrieval(UDOR) or Trans VaginalFollicle Aspiration(TVFA) and fertilization in the laboratory with transfer of embryos back into the uterus.

Role of Anaesthesiologist
1980's witnessed a drastic change from the use of laparoscope to vaginal ultrasound probe for egg retrieval. Although this technique of usingVaginal ultrasound probe is less invasive and associatedwith higher pregnancy rates, it forms one of the most stressful and painfulcomponents of the entire assisted reproductive treatment 2,3 Pain during oocyte retrieval is caused by the puncture ofthe vaginalskin and ovarian capsule by the aspiratingneedle aswellasmanipulation withinthe ovary during the entire procedure 4 . Here it becomes customary for the anaesthetist to provide adequate pain relief to immobilise the patient and eliminate the danger of piercing any vessel during the process of oocyte retrieval.The idealpain relief duringoocyteretrievalshould be effective and safe, easy to administer and monitor, short acting and readily reversible with a few side effects [5][6][7][8] .
Coexisting illness-Patients presenting in the IVF clinic needs to be investigated for any co morbid illnesses.In Indiatuberculosis is the mostimportant cause of infertility, so we need to know the drug interactions of anti tubercular drugs with the anaesthetic agents. These patients are generally kept on aspirin or heparin so as to prevent the hypercoaguable state occurring as a result of gonadotrophic injections.Aspirin should ideally be stopped 3 days prior to egg retrieval procedure. In case our patient is on heparin ,we needto know theActivated prothrombin time.
Thyroid can also be a cause of infertility so it becomes mandatory to assess the thyroid function tests and take appropriate anaesthetic precautions.
Anxiety -Another major challenge for the anaesthetistis to allay theanxiety .Thepatients presenting in the IVF clinic are under high degree of social and psychologicalstress. Majority of them are in late thirties, and theimmense familypressure makesthem more susceptible to psychomotor illness like depression and psychosis. Moreover this problem is further aggravated by the hormonal manipulation occuring duringin vitro fertilization.
Thus it becomes important to provide them with a comfortable environment so as to extract complete medical and pharmacologicalhistory.Nowadays many upcoming IVF centres have a provision for isolated rooms for the pre-anaesthetic checkups. One must remember that proper preoperative counseling is very important in allayinganxiety insuch patients.

Types of Anaesthesia
Presently anaesthesia for assisted reproductive tecnique is emerging as a speciality in itself. Patients presenting for IVF can havevaried causes for infertility like pelvic inflammatory disease due to tuberculosis, chlamydialinfection, history of previous pelvic surgery, tubalblockage or endometriosis. Therefore the patients undergoingthis treatmentare thoroughly evaluated for the cause of infertility and appropriate treatment instituted. Athorough preanaesthetic evaluationis required to identify any comorbid illness.
There are many options available to the anaesthesiologist: 1. Monitored sedation with/without localanaesthesia 2. GeneralAnaesthesia

RegionalAnaesthesia
A survey conducted by Bokhari et al in U.K showed the use of sedation in 46% of the centres, general anaesthesia in 28%, regional anaesthesia with sedation in 12% while a cocktailregime was followed by the rest 14% 9 .

Monitored anaesthesia care
Monitored anaesthesia is relatively easy to deliver, drugs are well tolerated and best suited in day care settings. However, it has its own risks of cardiac, respiratory and anaphylactic complications.  In USA, 95% of the programs use conscious sedation as a part of monitored anaesthesia care 10  In UK, 84% of the centres now use sedation 11 Monitoredanaesthesia techniquewith remifentanil resulted in a higher pregnancy rate than GA with alfentanil+ propofol or isoflurane +propofol for maintenance 12 .
Hadimioglo etalhad studied various combination of sedation regimens foroocyte retrieval.and found no significant difference between propofol +fentanyl, midazolam+fentanyland propofol+fentanyl in the recovery characteristics 13 . Midazolam was found to be safe for sedation in oocyte retrieval 14,15 .

General Anaesthesia
Invariably allanaesthetic agentsbeingused in general anaesthesia have been detected in follicular fluid, raising concerns regarding their use. However, with recent studies documentingthe safe use of the agents, balanced anaesthesia with N 2 O and opioids can be an option for anaesthesiologists. Hammadeh etalin 1999, showed a higher retrievalof oocytes with remifentanil +propofolor isoflurane based generalanaesthesia than with sedation with midazolam, diazepam or propofol 16 . This could be attributed to the increased comfort level of both the gynaecologist and the patient. With a relaxed uterus, it becomes easierfor the gynaecologist to aspirate even the smallovarian follicles, unlike sedation where a contracted myometrium fibrils pose a hinderence for oocyte retrieval. The key is to aim for a pharmacologicalexposure of shortest duration.

Use of Anaesthetic Drug
While selecting adesired agentour mainconcerns are:- Whether the substance enters the follicular fluid?

Drugs commonly used  Propofol
Widely being used in assisted reproduction and itseffects on the fertilization, embryo clevageand pregnancy rates has been extensively studied. Propofol has added advantages of antiemetic property along with faster recovery.
Though earlier studies had documented adverse effects of increased exposure to propofol on clevage of oocytes 17,18 , a recent study showed that although propofol follicular concentration increases with time, there was no difference in the ratesof mature to immature oocytes 19 .
In addition, there was no significant difference found in fertilization rate, clevage and embryo cell nu mb er,imp lantation rate as compared to thiopentone.Excepta trendtowards lowfertilization rate with longer exposure to anaesthetic drug 19,20  Role of Nitrous -Oxide Its role still remains controversial. Gonen etal found out that nitrous oxide has deleterious effect on IVF outcome 21 N 2 O inactivatesmethionine synthetase thereby decreasing the amount of thymidine available for DNA synthesis in dividingcells. However, as the inactivation of methionine proceeds slowly in the human liver, the effect of N 2 O is minimal. Further more, the low solubility of N 2 O exposes the oocytes to this gas for a brief duration. Rosen etal in 1987found no significant difference between the fertilization or pregnancy rateswhen comparing isoflurane with O 2 which was further confirmed by Matt etal 22,23 While, Hadimioglu N et al in 2002 showed nitrous oxide actually increase the rate of IVF by reducingthe concentration of other potentially toxicand less diffusibleanaesthetic drugs 14 .

 Benzodiazepine
Midazolam is the most commonly used benzodiazepine.Although minimalamountofthisbenzodiazipine are found in follicular fluid, no detrimentaleffects have been proven so far 24 . Acombination of midazolam and fentanylwas found to be safe for oocyte retrieval 5,25 .

 Narcotics
In recent years,various opioids have been used as a part of regime in conscious sedation and monitored carefor anesthesia in assistedreproductive technique.
Fentanylor alfentanilwerefound tobe favourable agents when used in combination with propofol by Hadimioglu etalin 2002. Fentanyl has minimalpenetration into follicular fluid 26,27 .Alfentanilfollicularfluid level is 10 fold smaller than the serum concentration at the same point 28 .

Drugs to be avoided Inhalational Agents
Majority of studieshave showndetrimental effect of halogenated fluorocarbons with N 2 O resulting in decreased clevage rates and increased abortions 30 .
Matt et al in 1991 found no significant effect of N 2 O and isoflurane anaesthesia on human IVF pregnancy rate 22 .

Use of Regional Anaesthesia
1. It constitutes either centralneuraxial blockade or the peripheralnueral block.
a. Para cervical block with different doses of lidocaine with sedation has been used by anaesthetist for egg retrieval [31][32][33][34] .Corson etal have even used paracervical block with bupivacaine for pain relief during oocyte aspiration 35 .Various conscioussedation regimens usingmidazolam, diazepam,alfentanylhave been used along with paracervical blockto enhance the analgesia 32 . Electroacupunture has also been used with paracervical blockto improve the effectiveness of pain relief 36 . b. Spinal anaesthesiais alsoan effectivemethod . Martin et al in 1998 had used low dose hyperbaric 1.5% lidocaine (45mg) spinal with low dose fentanyl 10mcg for egg retrieval 37 . Tsen had comparedlow dose bupivacaine +fentanyl with lidocaine+fentanylfor oocyte retrieval and did not find any combination superior to other 38 c. Epidural anaesthesia also forms a viable option but does not demonstrate any advantage over intravenous sedation 39 .
2. Bupivacaine compared favorably to lidocaine in allaspect except takingapproximately 30min longer to micturition and to discharge 40 .
The technique employed in aspiration of the oocyte and laborotry manipulations have all been modified and updated. Which is better, sedation or general anaesthesia is more of a personal preference. But the anaesthetic which is important tothe comfort levelboth for the patient and the gynaecologist to maximize the harvestingof oocytes playsan importantrole in the successful outcome.
How Safe are Anaesthetic Agents? With the coming up of large prospective trials documenting safe use of drugs like propofol, opioid, the newer anaesthetics havelost theirinhibitions regarding the use of these agents, thereby widening the scope of more rationale anaesthesia in IVF and extendingour services to thisdeveloping sub-speciality.